Resistance to multiple chemotherapeutic agents is a common clinical problem in the treatment of cancer. Such drug resistance may occur in primary therapy or be acquired during treatment. The problem is further exacerbated by the observation that these tumors are often cross-resistant to other drugs even though these drugs were not used in the initial treatment. Experimentally, this phenomenon is known as multidrug resistance (MDR) and appears to be use in part to an enhanced drug efflux mechanism which results in a reduced intracellular level of drug, although it is clear that multiple mechanisms can contribute to the MDR phenotype.
The hallmark of MDR is the overexpression of a membrane glycoprotein, termed P-glycoprotein (P-gp), which is thought to be responsible for the energy-dependent nonspecific exodus of drugs from MDR cells. Recent evidence from the transfection of the gene encoding for P-gp into drug-sensitive cells and the subsequent expression of the MDR phenotype in these cells confirms the importance of P-gp in MDR.
A broad range of agents that have been shown to modulate drug activity in MDR tumor cells. These include calcium channel blockers such as verapamil, steroids, and steroid antagonists (progesterone and tamoxifen), calmodulin antagonists (trifluoperazine), immunosuppressants (cyclosporin A), and cardiac agents (quinidine and aminodarone). These agents, however, have two major problems: (1) adequate blood levels for chemosensitization of MDR tumors cannot be achieved without considerable toxicity, and (2) most of these agents do not fully restore chemosensitivity of MDR tumors to anticancer drugs.
We have discovered a class of agents that addresses both of these problems. We have found a class of quinazolinedione compounds that are able to fully sensitize MDR cells to anticancer agents, and in limited clinical trials as antipsychotic drugs adequate plasma levels of representative examples of these drugs for chemosensitization of MDR tumors were achieved.